Crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide

ABSTRACT

A stable crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide is described. This crystal structure, designated Form B, is more stable, has favorable handling properties and is characterized by its melting point, x-ray and other physical characterizations.

This is a continuation of U.S. application Ser. No. 09/246,276 filedFeb. 8, 1999, now abandoned, which is a continuation of application Ser.No. 08,909,512, filed Aug. 12, 1997, now abandoned, which claimspriority of application Ser. No. 60/024,378, filed Aug. 14, 1998.

FIELD OF THE INVENTION

This invention is in the field of antiinflammatory pharmaceutical agentsand specifically relates to a crystalline form of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, methods ofpreparing the crystalline form, pharmaceutical compositions and methodsfor treating cyclooxygenase-2 (COX-2) associated disorders, includinginflammation.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects related toinhibition of cyclooxygenase-1 (COX-1).

A group of substituted isoxazoles are described in U.S. Pat. No.5,633,272, to Talley et al., and International Application WO96/25405.The compounds are described to be useful for the treatment ofinflammation and inflammation-associated disorders.4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide shows potential asa selective inhibitor of COX-2 over COX-1.

With all pharmaceutical compounds and compositions, the chemical andphysical stability of a drug compound is important in the commercialdevelopment of that drug substance. Such stability includes thestability at ambient conditions, especially to moisture and understorage conditions. Elevated stability at different conditions ofstorage is needed to anticipate the different possible storageconditions during the lifetime of a commercial product. A stable drugavoids the use of special storage conditions as well as frequentinventory replacement. A drug compound must also be stable during themanufacturing process which often requires milling of the drug toachieve drug material with uniform particle size and surface area.Unstable materials often undergo polymorphic changes. Therefore, anymodification of a drug substance which enhances its stability profileprovides a meaningful benefit over less stable substances.

It has now been discovered that4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide can be prepared indifferent crystal forms. An earlier material (Form “A”) is unstableafter mechanical grinding (milling) and is also thermally unstable. Arecently determined crystalline form (Form “B”) is described which ismore stable and has improved physical properties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a differential scanning calorimetry (DSC) profile of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form A.

FIG. 2 shows a differential scanning calorimetry (DSC) profile of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form B.

FIG. 3a shows an infrared spectrum of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form B.

FIG. 3b shows an infrared spectrum of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form A.

FIG. 4 shows an X-ray diffraction pattern of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form A.

FIG. 5 shows an X-ray diffraction pattern of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form B.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide can be prepared ina crystalline form designated “Form B”. Form B can be characterized bythe following methods.

Melting

Melting points were performed either on a Thomas Hoover melting pointapparatus or a Mettler FP900 Thermosystem melting point apparatus.Melting ranges were determined by differential scanning calorimetry on aTA Instruments Differential Scanning Calorimeter (Model 2100 controller,Model 912 dual calorimeter). The sample (1-2 mg) was placed in anunsealed aluminum pan and heated at 10° C./minute.

Form A showed an onset of melting at 160.2° C. with an imbedded exothermat 170.9° C. due to crystal rearrangement (see FIG. 1). Form B showed anonset of melting at 170.9° C. (peak 172.5° C.). An example of the DSC ofForm B is shown in FIG. 2.

Infrared Spectroscopy

Infrared spectra were obtained with a Nicolet DRIFT (diffusedreflectance infrared fourier transform) Magna System 550spectrophotometer. A Spectra-Tech Collector system and a 3 mm sample cupwere used. Samples (2%) were analyzed in KBr and scanned from 400 to4000 cm⁻¹. An example of an infrared absorption spectra of Form B isshown in FIG. 3a, and that of Form A is shown in FIG. 3b. The Y-axisrepresents corrected reflectance in Kubella-Munk units.

The infrared spectrum of Form B is characterized by absorptions at about3377, 1170, 1151, 925, 844, 745, 729, and 534 cm⁻¹ which are differentthan that observed in the Form A spectra. The infrared spectrum of FormA is characterized in part by an absorption at about 723 cm⁻¹ which isdifferent than that observed in the Form B spectra. Form B crystals ofthe present invention preferably display an infrared spectrumsubstantially the same as that shown in FIG. 3a.

X-ray Powder Diffraction

The analysis was performed with a Siemens D5000 powder diffractometer.Raw data was measured for 2θ values from 2 to 50, with steps of 0.020and step periods of 2 seconds.

Table I sets out the significant parameters of the main peaks in termsof 2θ values and intensities for Form B. An example of the x-raydiffraction pattern for Form A is shown in FIG. 4. An example of thex-ray diffraction pattern for Form B is shown in FIG. 5. Significantdifferences between Form A and Form B are evident at 12.221, 15.447,17.081, 19.798 and 23.861.

TABLE I Peak Angle-2θ Peak I/Imax No. (deg) D spacing Cps (%) 1 12.2217.2361 502.38 63.29 2 13.693 6.4617 38.03 4.79 3 14.227 6.2203 51.466.48 4 15.447 5.7314 599.94 75.58 5 15.801 5.6039 793.79 100.00 6 16.6785.3110 239.95 30.23 7 17.081 5.1868 331.31 41.74 8 18.165 4.8796 270.2134.04 9 19.066 4.6510 73.16 9.22 10 19.400 4.5717 200.13 25.21 11 19.7984.4807 789.23 99.43 12 20.578 4.3126 209.43 26.38 13 22.008 4.0354691.33 87.09 14 22.540 3.9414 71.87 9.05 15 22.975 3.8678 137.23 17.2916 23.580 3.7699 394.27 49.67 17 23.861 3.7261 602.27 75.87 18 24.5533.6226 397.23 50.04 19 25.206 3.5302 192.44 24.24 20 25.560 3.4822 77.749.79 21 25.940 3.4320 31.47 3.96 22 26.200 3.3985 20.87 2.63 23 27.2953.2646 151.54 19.09 24 28.595 3.1191 207.74 26.17 25 29.124 3.0636161.44 20.34 26 29.656 3.0099 73.94 9.32

Form B can be prepared by the recrystallization of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide from a suitablesolvent. To prepare Form B,4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide is dissolved in avolume of solvent and cooled until crystals form. Preferably, thecompound is added to a solvent at a temperature of at least about 25° C.More preferably, the temperature of the solvent is between 30° C. andthe boiling point of the solvent. An even more preferred temperature isin a range of about 65-75° C.

Alternatively, hot solvent may be added to the compound and the mixturecan be cooled until crystals form. Preferably, the solvent is at atemperature of at least 25° C. More preferably, the temperature of thesolvent is at a temperature in the range of about 50-80° C. Even morepreferred, the temperature is in a range of about 65-75° C.

Preferably, the compound is mixed with an amount of solvent over about 3times the weight of the compound. More preferred, the solvent tocompound ratio is about 7 to about 10 times.

Preferably the solution is cooled slowly to precipitate Form B. Morepreferably, the solution is cooled at a rate slower than about 0.5°C./minute. Even more preferably, the solution is cooled at a rate ofabout 0.3° C./minute or slower.

A suitable solvent is a solvent or mixture of solvents which dissolvesthe compound and any impurities at an elevated temperature, but uponcooling, preferentially precipitates Form B. A suitable solvent isselected from an alcohol, methyl tert-butyl ether, methyl ethyl ketoneand a combination of solvents selected from alcohol, methyl tert-butylether, acetonitrile, water, acetone, tetrahydrofuran and methyl ethylketone. An alcohol or aqueous alcohol is preferred. A more preferredsolvent is selected from methanol, aqueous methanol, ethanol, aqueousethanol, isopropyl alcohol and aqueous isopropyl alcohol. Even morepreferred is aqueous methanol, methanol, ethanol 3A, aqueous ethanol anda mixture of isopropanol/methanol.

Alternatively, the compound is dissolved in one solvent and a co-solventis added to aid in the crystallization of the desired form.

The crystals of Form B so formed are separated from the solvent such asby filtration or centrifugation. Preferably, the crystals are dried, andmore preferably at a temperature in the range of about 30° C. to about100° C. Even more preferably, the crystals are dried under vacuum.

Alternatively, Form B can be prepared by heating Form A at a temperaturesufficient to convert to Form B. Preferably, Form A is heated at atemperature in the range of 50° C. to about 140° C.

Preparation

The following examples contain detailed descriptions of the methods ofpreparation of Form B. These detailed descriptions fall within thescope, and serve to exemplify the invention. These detailed descriptionsare presented for illustrative purposes only and are not intended as arestriction on the scope of the invention. All parts are by weight andtemperatures are in degrees Centigrade unless otherwise indicated.

4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide was prepared by thefollowing method where ethanol 3A is an aqueous ethanol (5% water)denatured with methanol:

EXAMPLE 1

Step 1. Preparation of Deoxybenzoin Oxime

Sodium acetate trihydrate (152.5 g, 1.12 mole, 1.1 eq.) was added todeoxybenzoin (200 g, 1.02 mole) and dissolved with ethanol (3A, 0.8 L)and water (0.24 L) in a 5 L flask with mechanical stirrer, refluxcondenser, and thermometer. The solution was stirred and heated to 70±1°C. Water (0.1 L) was added to hydroxylamine hydrochloride (78.0 g, 1.12mole, 1.1 eq.) in a separate 500 ML flask with stirring. Thehydroxylamine hydrochloride solution was transferred to the deoxybenzoinsolution, while the reaction mixture was kept at about 70° C. Themixture was heated to boiling (about 84° C.) and held at thistemperature for 40 minutes. The mixture was cooled to 40° C. in twohours and charged water (10.5 L) into the reaction mixture. The reactionmixture was cooled to 20° C. over another hour with stirring. Crystalsof pure oxime formed which were isolated by filtration (Buchner funnel,No. 1 Whatman filter paper) using house vacuum, washed with a mixture of50 mL of 3A ethanol and 100 mL of water, and with water (1 L). The solidwas dried with vacuum for 2 hours, and at 55° C. under house vacuum for12 hours to yield pure deoxybenzoin oxime (213.2 g, 99%).

Step 2. Preparation of 5-hydroxy-5-methyl-3,4-diphenylisoxazoline

The deoxybenzoin oxime (Step 1) was dissolved in anhydrous THF (565 mL)under a nitrogen atmosphere. The solution was cooled to −20° C. Thesolution was treated with lithium diisopropylamide (2 M, 800 mL, 1.60mol) while allowing the reaction temperature to warm to 10-15° C. Thereaction mixture to was cooled to −10° C. to −20° C. and anhydrous ethylacetate (218 mL) was added to the solution while allowing the reactiontemperature to rise to a maximum of 25° C. and held for 30 minutes at25° C. The reaction mixture was cooled to about 0° C. Water was added toa quench flask and cooled to 0-5° C. The pre-cooled reaction mixture wastransferred from the reaction flask to the quench flask whilemaintaining the temperature of the quench mixture below 25° C. Thequenched mixture was cooled to 0-5° C. Hydrochloric acid (12 M). wasadded to the mixture, keeping the temperature below 25° C. during theaddition by controlling the addition rate and stirred until all thesolids dissolve (˜5 minutes). The pH of the stirred mixture was measuredto be pH 3-4. The layers were separated and the organic layer wasremoved. Heptane was added to the organic layer with stirring. Theorganic layer was distilled until the pot temperature reached 90-91° C.The solution was cooled to 5° C. and filtered. The solid was washed withtwo 300 mL portions of ethyl acetate-heptane (20/80), cooled to 5° C.The solid product was dried on the funnel for several hours then driedat ambient under vacuum with a nitrogen sweep over the weekend to yieldthe isoxazoline (108.75 g, 57.7%).

Step 3. Preparation of4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonamide

5-Hydroxy-5-methyl-3,4-diphenylisoxazoline (Step 2) (142 g, 0.56 mol)was dissolved in dichloromethane (568 mL) in a 3 L roundbottom flaskequipped with a heating mantle, mechanical stirrer, cold watercondenser, J-KEM temperature controller and thermocouple, forming aslurry. The slurry was stirred and cooled to <10° C. Chlorosulfonic acid(335 mL, 586.3 g, 5.04 mol) was added to the slurry, keeping thetemperature of the flask below 20° C. by controlling the addition. Themixture was heated to reflux (ca. 40° C.), maintained for 5 hours, thencooled to 0-5° C. The cooled reaction solution was slowly transferred toa 3 L 3-necked roundbottom flask (mechanical stirrer and thermocouple)containing water (1000 ml) previously cooled to 0-5° C., using vigorousagitation and keeping the pot temperature below 10° C. The mixture wasstirred for an additional 5 minutes. The layers were separated. In aseparate 3 L flask (mechanical stirrer, external ice/salt bath,thermocouple) 28% ammonium hydroxide (700-mL) was cooled to 0-5° C. Themethylene chloride solution was transferred to the stirred ammoniumhydroxide solution, keeping the temperature below 10° C. The mixture wasstirred at ambient temperature for 60 minutes. The resulting slurry wasfiltered and the solid was washed with water (200 ml) and dried,yielding the 4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonamide as awhite solid (94.3 g, 53.5%).

Step 4. Recrystallization of4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonamide

The 4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonamide from Step 3was dissolved in 300 mL of boiling methyl ethyl ketone (2-butanone) anddiluted with 10% aqueous isopropyl alcohol (300 mL, (270 mL anhydrousisopropyl alcohol and 30 mL of water)). The material was cooled to roomtemperature, whereupon crystals formed. The crystals were isolated byfiltration and dried in a vacuum drying oven (10 mm Hg, 100° C.) toafford pure Form B (112.95 g, 65%): mp 172-173° C.

EXAMPLE 2

“4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 1, step3) (3 g) was combined with 80% ethanol 3A/20% water (9 ml) and heateduntil solids dissolved. The flask was cooled with a tap water bath andheld for 1 hour to form a precipitate. The solid was filtered off andwashed with ethanol 3A. The material was heated to dryness under vacuum(50-60° C., 20 in Hg). The material formed was identified as Form B.”

EXAMPLE 3

“4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 1, step3) (10 g) was combined with ethanol 3A (100 ml ) and heated until thesolids dissolved (about 70° C.). The flask was cooled to 20-25° C. over1.5 hours and held for 30 minutes to form a precipitate. The solid wasfiltered off (Whatman # 1 filter paper) and washed with water. Thematerial was heated to dryness under vacuum (90° C., 50-100 mm Hg). Thematerial formed was identified as Form B.”

EXAMPLE 4

“4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 1, step3) (9.8 g), methanol (73.5 mL) and water (24.5 mL) were combined andheated to 65-70° C. The solution was held for about 10 minutes andfiltered while hot to remove any particulate matter. The solution wascooled slowly to 50° C. (about 0.3° C./min) held at 50° C. for 1 hour(crystallization begins during the hold period). The solution wasfurther cooled to 5° C. (about 0.3° C./min) and held at 5° C. for 1hour. The product was isolated by filtration and washed with 10 mL ofcold methanol/water (75/25). The product was dried at 95-100° C. for 4hours to give 8.55 g of Form B.”

EXAMPLE 5

Methanol/isopropanol (80/20, 120 ml) was added to4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 1, step 3)(25 g) and heated to about 68° C. The solution was held for about 15minutes and filtered with a glass filtering funnel, while hot, to removeany particulate matter. The solution was cooled slowly to 5° C. over 3.3hours (about 0.3° C./min) and held at 5° C. for 2 hours. The product wasisolated by filtration and washed with 10 mL of coldmethanol/isopropanol (80/20). The product was dried at 95-100° C. for 3hours to give 11 g of Form B.

Comparative Example 6

“4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 1, step3)(10 g) was combined with 20 mL of water:methanol (25:75), and heateduntil the solids dissolved. The flask containing the solution was set inice and the mixture cooled rapidly to <10° C. with no crystallizationobserved on cooling. A few crystals were observed forming on bottom offlask, and soon crystallization was rapid. Let stand for about 10minutes. The solid was filtered off and washed with 75% aqueousmethanol. The material was heated to dryness under vacuum w/nitrogenbleed (50-60° C., 20 in Hg). Material formed was identified as Form A.”

The present invention also comprises a method of treating or preventinga cyclooxygenase-2 associated disorder such as inflammation in asubject, the method comprising treating the subject having orsusceptible to such inflammation or disorder with atherapeutically-effective amount of crystalline Form B of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide.

Form B of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide would beuseful for, but not limited to, the treatment of inflammation in asubject, and for treatment of other cyclooxygenase-2 mediated disorders,such as, as an analgesic in the treatment of pain and headaches, or asan antipyretic for the treatment of fever. For example, Form B would beuseful to treat arthritis, including but not limited to rheumatoidarthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,systemic lupus erythematosus and juvenile arthritis. Form B would beuseful in the treatment of asthma, bronchitis, menstrual cramps, pretermlabor, tendinitis, bursitis, liver disease including hepatitis,skin-related conditions such as psoriasis, eczema, burns and dermatitis,and from post-operative inflammation including from ophthalmic surgerysuch as cataract surgery and refractive surgery. Form B also would beuseful to treat gastrointestinal conditions such as inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome andulcerative colitis. Form B would be useful for the prevention ortreatment of cancer, such as colorectal cancer, and cancer of thebreast, lung, prostate, bladder, cervix and skin. Form B would be usefulin treating glaucoma, angiogenesis and retinopathies. Form B would beuseful in treating inflammation in such diseases as vascular diseasesincluding atherosclerosis, migraine headaches, periarteritis nodosa,thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumaticfever, type I diabetes, neuromuscular junction disease includingmyasthenia gravis, white matter disease including multiple sclerosis,sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis,gingivitis, nephritis, hypersensitivity, swelling occurring afterinjury, myocardial ischemia, and the like. Form B would also be usefulin the treatment of ophthalmic diseases, such as retinitis,conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acuteinjury to the eye tissue. Form B would also be useful in the treatmentof pulmonary inflammation, such as that associated with viral infectionsand cystic fibrosis. Form B would also be useful for the treatment ofcertain central nervous system disorders, such as cortical dementiasincluding Alzheimer's disease, and central nervous system damageresulting from stroke, ischemia, seizures and trauma. Form B is usefulas antiinflammatory agents, such as for the treatment of arthritis, withthe additional benefit of having significantly less harmful sideeffects. Form B would also be useful in the treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome,osteoporosis and inhibiting bone resorption. Form B also would be usefulin the treatment of pain, but not limited to postoperative pain, dentalpain, muscular pain, and pain resulting from cancer. Form B would beuseful for the prevention of cardiovascular disease, such asatherosclerosis, liver disease and dementias, such as Alzheimer'sDisease.

Besides being useful for human treatment, this form is also useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

The present Form B may also be used in co-therapies, partially orcompletely, in place of other conventional antiinflammatories, such astogether with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB₄ receptorantagonists and LTA₄ hydrolase inhibitors.

Suitable LTA₄ hydrolase inhibitors include RP-64966,(S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl ester(Scripps Res. Inst.),N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine(Searle), 7-(4-(4-ureidobenzyl)phenyl)heptanoic acid (Rhone-PoulencRorer), and 3-(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithiumsalt (Searle).

Suitable LTB₄ receptor antagonists include, among others, ebselen,linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-615, Merck compound MAFP, Terumocompound TMK-688, Tanabe compound T-0757, Lilly compounds LY-213024,LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and292728, ONO compounds ONO-LB457, ONO-4057, and ONO-LB-448, Shionogicompound S-2474, calcitrol, Lilly compounds Searle compounds SC-53228,SC-41930, SC-50605 and SC-51146, Warner Lambert compound BPC 15,SmithKline Beecham compound SB-209247 and SK&F compound SKF-104493.Preferably, the LTB₄ receptor antagonists are selected from calcitrol,ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmarkcompound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, andTerumo compound TMK-688.

Suitable 5-LO inhibitors include, among others, Abbott compoundsA-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CMI-392, EisaiE-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000,Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen,linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton,pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadremphosphate, and bunaprolast.

The present form also may be used in combination therapies with opioidsand other analgesics, including narcotic analgesics, Mu receptorantagonists, Kappa receptor antagonists, non-narcotic (i.e.non-addictive) analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, Substance P antagonists,neurokinin-1 receptor antagonists and sodium channel blockers, amongothers. More preferred would be combinations with compounds selectedfrom morphine, meperidine, codeine, pentazocine, buprenorphine,butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone,Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180,HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631,Tramadol [(−) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994.

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of crystalline Form B of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide in association withat least one pharmaceutically-acceptable carrier, adjuvant or diluent.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising crystalline Form B in association with one ormore non-toxic, pharmaceutically-acceptable carriers and/or diluentsand/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. Form B of thepresent invention may be administered by any suitable route, preferablyin the form of a pharmaceutical composition adapted to such a route, andin a dose effective for the treatment intended. The active Form B andcompositions may, for example, be administered orally, intravascularly,intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compound that is administered andthe dosage regimen for treating a disease condition with the compoundand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the disease, the route and frequency of administration, andthe particular compound employed, and thus may vary widely. Thepharmaceutical compositions may contain active ingredients in the rangeof about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mgand most preferably between about 1 and 100 mg. A daily dose of about0.01 to 100 mg/kg body weight, preferably between about 0.5 and about 20mg/kg body weight and most preferably between about 0.1 to 10 mg/kg bodyweight, may be appropriate. The daily dose can be administered in one tofour doses per day.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of Form B to the affected area two tofour times a day.

For inflammations of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream, or as a suppository, containing the active ingredients in a totalamount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w andmost preferably 0.4 to 15% w/w. When formulated in an ointment, theactive ingredients may be employed with either paraffinic or awater-miscible ointment base. Alternatively, the active ingredients maybe formulated in a cream with an oil-in-water cream base. If desired,the aqueous phase of the cream base may include, for example at least30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethylsulfoxide and relatedanalogs.

Form B can also be administered by a transdermal device. Preferablytopical administration will be accomplished using a patch either of thereservoir and porous membrane type or of a solid matrix variety. Ineither case, the active agent is delivered continuously from thereservoir or microcapsules through a membrane into the active agentpermeable adhesive, which is in contact with the skin or mucosa of therecipient. If the active agent is absorbed through the skin, acontrolled and predetermined flow of the active agent is administered tothe recipient. In the case of microcapsules, the encapsulating agent mayalso function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0-5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w.

For therapeutic purposes, Form B is ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compound may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The crystalline Form B may be dissolved in water, polyethylene glycol,propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, sodium chloride, and/or various buffers. Otheradjuvants and modes of administration are well and widely known in thepharmaceutical art.

All mentioned references are incorporated by reference as if herewritten.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A crystalline form of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide having a meltingpoint of about 170-174° C.
 2. A form of claim 1 having an IR spectrumwith the following peaks: 1170, 925, 844, and 729 cm⁻¹.
 3. A form ofclaim 1 having an IR spectrum without a significant peak at 723 cm⁻¹. 4.A form of claim 1 having an x-ray powder diffraction pattern with thefollowing peaks: 12.221, 15.447, 17.081, 19.798 and 23.861.
 5. Apharmaceutical composition comprising a therapeutically-effective amountof crystalline Form B of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide in association withat least one pharmaceutically-acceptable carrier, adjuvant or diluent.6. A method of treating a cyclooxygenase-2 associated disorder in asubject, said method comprising treating the subject having orsusceptible to said disorder with a therapeutically-effective amount ofthe crystalline Form B of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide.
 7. The method ofclaim 6 for use in treatment of inflammation.
 8. The method of claim 6for use in treatment of arthritis.
 9. The method of claim 6 for use intreatment of pain.
 10. The method of claim 6 for use in treatment offever.
 11. A method of preparing crystals of claim 1 comprisingdissolving 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide in analcohol based solvent system form a solution and slowly cooling thesolution.
 12. The method of claim 11 wherein the solvent systemcomprises one or more solvents selected from methanol, isopropanol,aqueous methanol and aqueous ethanol.
 13. The method of claim 11 whereinthe crystals are recrystallized from a mixture of isopropanol andmethanol.